Lipopolysaccharide (LPS, endotoxin) is the major antigen of Gram-negative bacteria. LPS is a glycophospholipid consisting of an antigenic, variable size, carbohydrate chain covalently linked to lipid A, the conserved hydrophobic region structurally defined as N,O-acyl beta-1,6-D-glucosamine 1,4′-bisphosphate. Toxicity of LPS is expressed by lipid A through the interaction with B-cells and macrophages of the mammalian immune system, a process leading to the secretion of proinflammatory cytokines, mainly TNF, which may have fatal consequences for the host. Lipid A also activates human T-lymphocytes (Th-1) “in vitro” as well as murine CD4+ and CD8+ T-cell “in vivo”, a property which allows the host's immune system to mount a specific, anamnestic IgG antibody response to the variable-size carbohydrate chain of LPS. On these bases, LPS has been recently recognized as a T-cell dependent antigen “in vivo”.
In order to fully express toxicity, LPS must retain its supramolecular architecture, through the association of several units of glycophospholipid monomers forming the lipid A structure. This conformational rearrangement of the molecule is also fundamental for full expression of the immunogenic characteristic.
Sepsis and septic shock are well defined clinical conditions that are caused by bacteria and by LPS, which is the endotoxin elaborated by the bacteria responsible for the above-mentioned pathologies.
The clinical signs of sepsis and septic shock vary, depending on the amount of endotoxin present and the time elapsed in the disease process. The earliest clinical signs of an infection may be fever, mild depression, and lack of appetite. Further into the disease process, the patient will exhibit more obvious signs of shock, including increased heart rate, weak pulse pressure, dehydration, darkening of the gums, cold feet and ears, below-normal temperature, increased respiratory rate, or diarrhea. Once a patient has exhibited signs of endotoxic shock, it should be considered an emergency and a physician should be contacted immediately.
Despite the judicious use of antibiotics and other therapeutic measures, mortality from endotoxin related disorders remains a significant problem. Antibiotic resistance of bacteria, severity of the underlying diseased processes, and inadequate administration of supportive therapy account in part for the failure of conventional treatments. What is needed is an improved understanding of the Gram-negative bacteria that cause endotoxin related disorders. Additionally, improved treatment for endotoxin related disorders are needed.